CN109486948A - The polymolecular marker and its device and evaluation method of a kind of individuation prediction colorectal cancer prognosis of function-driven - Google Patents
The polymolecular marker and its device and evaluation method of a kind of individuation prediction colorectal cancer prognosis of function-driven Download PDFInfo
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Abstract
The polymolecular marker and its device and evaluation method of a kind of individuation prediction colorectal cancer prognosis of function-driven, the present invention concentrates from the multiple cancer big-sample datas of multicenter while screening prognosis prediction marker, and the prediction effect of the polymolecular marker is verified and fully assessed in 3 independent data sets, the application of above method and strategy ensure that reliability of the present invention in the judgement of colorectal cancer patients prognosis, polymolecular marker combination not will receive the influence of the batch effect or detection platform difference of experiment, it ensure that stability of the present invention in the judgement of colorectal cancer patients prognosis；Polymolecular marker combination does not need to carry out before use the data normalization processing between multisample, easy to use, ensure that clinical operability of the present invention in the judgement of colorectal cancer patients prognosis.
Description
Technical field
The present invention relates to cma gene group and oncology technical field, in particular to a kind of individual of function-driven
Change the polymolecular marker for predicting colorectal cancer prognosis and its device and evaluation method.
Background technique
Colorectal cancer is one of most common malignant tumour in the world, with the development of economy with the variation of eating habit,
The disease incidence of colorectal cancer increases year by year, and the death rate is located at the 5th of Cancer in China associated death.In the world, knot is straight
Intestinal cancer arranges the 4th in male malignancy causes of death, and the 3rd is arranged in women.The colorectal cancer death rate of developing country
Higher (the colorectal cancer death for accounting for about 52%) illustrates that the survival rate of these regional colorectal cancers is very low.The whole world has every year
1200000 cases newly made a definite diagnosis, and have more than 600,000 patients and die of colorectal cancer.Colorectal cancer incidence rate is in the right side of fifty year
Age section is lower, but can increase with the increase at age.The Colorectal Cancer the median age of developed country is 70 years old, which exists
Europe, North America and Oceania are more multiple, and then more rare in South Asia, the Central Asia and Africa.Current clinically used treatment side
Formula is radical-ability tumorectomy.However according to relevant report, after Radical Colectomy for Carcinoma of Colon, 5 years survival rates of patient only 50% to
60% or so.For therapeutic modalities such as operation, chemotherapy, radiotherapies, about 75% colorectal cancer patients are diagnosed in early stage,
Operation or/and chemotherapy can be carried out, some patient has been in inoperable late stage when making a definite diagnosis, can only receive
Chemotherapy or radiotherapy.Therefore intervene the undesirable Nature prognosis of colorectal cancer, improve undesirable treatment prognosis, improve medical level, mention
High quality of life, the life cycle for extending patient is a problem in the urgent need to address in the accurate medical domain of colorectal cancer.
And realize that the main foundation of the accurate diagnosis and treatment of individuation is the heterogeneity of colorectal cancer.Clinically used pathological staging is that prediction knot is straight
The prognosis of patients with bowel cancer and guiding treatment provide good foundation, but they be all with tumor invasive depth, lymphatic metastasis,
Based on DISTANT METASTASES IN.Numerous studies have been found that colorectal cancer occurrence and development and patient's prognosis it is heterogeneous often by
To the synergistic effect of polygenes and environmental factor.The same patient by stages of clinical discovery carries out same Regimen Chemotherapy effect difference,
Prognosis is different.Therefore only with doctor according to the Clinical symptoms and clinical experience of patient, the molecular heterogeneity of patient is not considered,
It is difficult to accurate judgement patient's prognosis.With the development of molecular biology and high throughput sequencing technologies, molecular marker at
For the hot spot of tumor prognosis research, molecular marker relevant to colorectal cancer patients existence is screened, to the early stage of colorectal cancer
It diagnoses, the equal important in inhibiting of selection of prognosis evaluation and drug target.
Although there is some molecular markers studied and some colorectal cancer prognosis have been proposed at present, these researchs are main
Based on individual data collection, single technology platform or Small Sample Database collection, therefore the cancer prognosis model established is usually excessive
Dependent on the technical characterstic of platform where sample, there is a degree of bias, often generate over-fitting, it is difficult to obtain
The stronger molecular marker of robustness, therefore the prognosis of colorectal cancer patients can not be carried out in different platform data accurate pre-
It surveys.Existing molecular marked compound combination frequently includes the more gene of number simultaneously, and between different molecular labels combination
Repetitive rate is smaller, is not suitable for application detection clinically.Finally have molecular marked compound combination and is often based upon the linear of training set
Scoring model, and scoring threshold is set, however the scoring model is applied to need to count data set when independent data sets
According to standardization, the risk profile that individuation is carried out to single patient can not be carried out.Therefore the molecular marked compound combination found in the past
Unilateral to the prediction and evaluation comparison of colorectal cancer prognosis, sensibility and specificity is often not ideal enough.And with high-throughput gene
The development of detection of expression technology and deepening continuously for biological information research, multidata confluence analysis become cancer prognosis
One big advantage, therefore by being screened using existing transcription group and Clinical symptoms big data to prognostic gene, and from life
The angle of object function-driven screens molecular marker, to correct by calculating bring false positive results, more can objectively look for
Stable out, robust, the extensive marker of applicability, and utilize the prognostic risk mould of novel mathematical method building individuation
Type can provide more effective and accurate disease for single colorectal cancer patients and develop prognostic evaluation index, to facilitate
Clinicians make personalized therapy program monitors chemotherapeutic efficacy and judging prognosis, improves the survival rate of colorectal cancer patients.
Summary of the invention
In order to make up for the deficiencies of the prior art, the purpose of the present invention is to provide a kind of predictions of the individuation of function-driven to tie
The polymolecular marker and its device and evaluation method of carcinoma of the rectum prognosis, polymolecular marker provided by the present invention combination for
The prognosis prediction of colorectal cancer patients sensitivity and specificity with higher can be used as novel molecular marker for instructing to do
The bad Nature prognosis of pre- colorectal cancer patients improves undesirable treatment prognosis.
The technical solution that the present invention uses is: more points of the individuation prediction colorectal cancer prognosis of a kind of function-driven
Sub- marker, which is characterized in that the polymolecular marker includes the guarantor in colorectal cancer generating process of the Hazard ratio less than 1
Risk factor molecular marker in the colorectal cancer generating process of shield factor molecular marker and Hazard ratio greater than 1, it is described
Protection factor molecular marker includes 18 markers gene C EBPA, KLHDC3, FITM2, GALM, CYP1A1, ANKS4B,
IL12A,CC2D1A,ZC4H2,PRLR,VANGL2,NDRG2,CCL22,GORASP1,ST6GAL1,TRAF1,L3MBTL4,
ARHGEF11, the risk factor molecular marker include 28 markers gene C DKN2A, NDRG1, FAM3C, CHD2,
FZD10,DSG3,ACSL4,FOXD1,FLT1,KLK5,WSB1,MYOF,KRT6C,GRB10,ANXA2,HOXC6,ITGA3,
KRT6A,KRT6B,MARK3,MSH4,GULP1,KLK7,KLK6,ANXA8,TJP1,PTTG1IP,DLG5。
A kind of polymolecular marker personalization prediction Patients with Colorectal Cancer prognostic risk evaluating apparatus, the device include
Predict that the risk assessment scoring model of Patients with Colorectal Cancer prognosis, the formula of the evaluation scoring model are as follows:
PrognosticScore (S)=ssES (Ggood, S) and-ssES (Gpoor, S)；
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor
Molecular marker set, S are any one given single sample, and i is designated position, r (gj) it is that expression value is arranged from high to low
Order obtained after sequence and standardization, w are weight order value, which is set as 3；N is gene detected by single sample
Total number, NGFor the total number of prognosis molecule marker.
A kind of risk evaluating method of the Patients With Rectal Carcinoma prognosis of the polymolecular marker using prediction colorectal cancer prognosis,
The following steps are included:
(1) the colorectal cancer gene expression profile data with clinical information such as life span and survival conditions is obtained, wherein
Including 9 sets of Patients with Colorectal Cancer microarray datas, a set of Patients with Colorectal Cancer RNA-seq expresses data；
(2) data set of comprehensive life span will be contained in the data of acquisition as training set, be utilized respectively single Cox and more
Cox regression analysis screening has significant associated gene with comprehensive life span；
(3) significant associated gene carries out meta points with comprehensive life span for what is recognized in the expression data of acquisition
Analysis selects 69 genes of the p value less than 0.001 as candidate prognosis related molecule marker；
(4) 69 colorectal cancer candidate's prognosis molecule markers of acquisition are subjected to function enrichment analysis, filtered out significant
The candidate molecules marker being enriched in the relevant semantic entry of biological process in GO functional semantics, as final Colon and rectum
Cancer prognosis molecule marker, totally 46 genes；
(5) that 46 of acquisition final colorectal cancer prognosis molecule markers are divided into 18 Hazard ratios is straight less than 1 knot
Protection factor molecular marker gene C EBPA, KLHDC3, FITM2, GALM, CYP1A1, ANKS4B in intestinal cancer generating process,
IL12A,CC2D1A,ZC4H2,PRLR,VANGL2,NDRG2,CCL22,GORASP1,ST6GAL1,TRAF1,L3MBTL4,
Risk factor molecular marker gene C DKN2A in colorectal cancer generating process of ARHGEF11 and 28 Hazard ratio greater than 1,
NDRG1,FAM3C,CHD2,FZD10,DSG3,ACSL4,FOXD1,FLT1,KLK5,WSB1,MYOF,KRT6C,GRB10,
ANXA2,HOXC6,ITGA3,KRT6A,KRT6B,MARK3,MSH4,GULP1,KLK7,KLK6,ANXA8,TJP1,PTTG1IP,
DLG5；
(6) the polymolecular marker of above-mentioned steps (5) is integrated, being constructed using ssGSEA algorithm can be applied to
The risk scoring model of personalization prediction Patients with Colorectal Cancer prognosis.The formula of the evaluation model is as follows:
Prognostic Score (S)=ssES (Ggood, S) and-ssES (Gpoor, S)；
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor
Molecular marker set, S are any one given single sample, and i is designated position, r (gj) it is that expression value is arranged from high to low
Order obtained after sequence and standardization, w are weight order value, which is set as 3；N is gene detected by single sample
Total number, NGFor the total number of prognosis molecule marker；
(7) by the expression of this 46 polymolecular markers carry out integration establish can clinical application colorectal cancer patients
The prediction scoring model of prognosis, using the median of training set risk score as cut off value, by patient be divided into existence result it is good with
Result of surviving is poor, if Prognostic Score < median, the prognosis existence result for disclosing the patient is poor；If
It is preferable to disclose patient's prognosis existence by Prognostic Score > median.
The beneficial effects of the present invention are: the present invention provides a kind of prediction colorectal cancer prognosis of the individuation of function-driven
Polymolecular marker and its device and evaluation method, the present invention is concentrated from the multiple cancer big-sample datas of multicenter while screening is pre-
Predicting marker afterwards, and verifying has been carried out in 3 independent data sets to the prediction effect of the polymolecular marker and has been commented comprehensively
Estimate, the application of above method and strategy ensure that reliability of the present invention in the judgement of colorectal cancer patients prognosis, this is more
Molecular marker combination not will receive the influence of the batch effect or detection platform difference of experiment, ensure that the present invention is straight in knot
Stability in the judgement of patients with bowel cancer prognosis；Polymolecular marker combination does not need to carry out the number between multisample before use
It is easy to use according to standardization, it ensure that clinical operability of the present invention in the judgement of colorectal cancer patients prognosis, energy
More effective and accurate disease enough is provided for single colorectal cancer patients and develops prognostic evaluation index, to facilitate clinical doctor
It is raw to formulate personalized therapy program, chemotherapeutic efficacy and judging prognosis are monitored, the survival rate of colorectal cancer patients is improved.
Specific embodiment
It in order to illustrate more clearly of the content of present invention, is described as follows with specific embodiment, specific embodiment does not limit this hair
Bright context.
A kind of polymolecular marker of the individuation prediction colorectal cancer prognosis of function-driven, the polymolecular marker
The Colon and rectum of protection factor molecular marker and Hazard ratio greater than 1 in colorectal cancer generating process including Hazard ratio less than 1
Risk factor molecular marker during carcinogenesis, the protection factor molecular marker include 18 marker genes
CEBPA,KLHDC3,FITM2,GALM,CYP1A1,ANKS4B,IL12A,CC2D1A,ZC4H2,PRLR,VANGL2,NDRG2,
CCL22, GORASP1, ST6GAL1, TRAF1, L3MBTL4, ARHGEF11, the risk factor molecular marker include 28
Marker gene C DKN2A, NDRG1, FAM3C, CHD2, FZD10, DSG3, ACSL4, FOXD1, FLT1, KLK5, WSB1, MYOF,
KRT6C,GRB10,ANXA2,HOXC6,ITGA3,KRT6A,KRT6B,MARK3,MSH4,GULP1,KLK7,KLK6,ANXA8,
TJP1,PTTG1IP,DLG5。
A kind of polymolecular marker personalization prediction Patients with Colorectal Cancer prognostic risk evaluating apparatus, the device include
Predict that the risk assessment scoring model of Patients with Colorectal Cancer prognosis, the formula of the evaluation scoring model are as follows:
PrognosticScore (S)=ssES (Ggood, S) and-ssES (Gpoor, S)；
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor
Molecular marker set, s are any one given single sample, and i is designated position, r (gj) it is that expression value is arranged from high to low
Order obtained after sequence and standardization, w are weight order value, which is set as 3；N is gene detected by single sample
Total number, NGFor the total number of prognosis molecule marker.
A kind of risk evaluating method of the Patients With Rectal Carcinoma prognosis of the polymolecular marker using prediction colorectal cancer prognosis,
The following steps are included:
1) Colon and rectum with clinical information such as life span and survival conditions is obtained from public database GEO and TCGA
Oncogene expression modal data, including 9 sets of Patients with Colorectal Cancer microarray datas, a set of Patients with Colorectal Cancer RNA-seq
Express data.
2) using above-mentioned steps 1) obtain HG-U133_Plus_2 platform in have 7 sets of data collection of comprehensive life span as
Training set (GSE39582, GSE17536, GSE72970, GSE38832, GSE39084, GSE29621, GSE17537), it is sharp respectively
There is significant associated gene with comprehensive life span with single Cox and more Cox regression analyses screening.
3) by above-mentioned steps 2) obtain 7 sets expression data on recognize with comprehensive life span have significantly associated base
Because carrying out meta analysis, select 69 genes of the p value less than 0.001 as candidate prognosis related molecule marker.
4) by above-mentioned steps 3) obtain colorectal cancer candidate's prognosis molecule marker carry out function enrichment analysis, use
ClusterProfiler software package filters out in the relevant semantic entry of significant enrichment biological process in GO functional semantics
Candidate molecules marker, as final colorectal cancer prognosis molecule marker, totally 46 genes.
5) above-mentioned steps 4) polymolecular marker in, 18 marker genes (CEBPA, KLHDC3, FITM2, GALM,
CYP1A1,ANKS4B,IL12A,CC2D1A,ZC4H2,PRLR,VANGL2,NDRG2,CCL22,GORASP1,ST6GAL1,
TRAF1, L3MBTL4, ARHGEF11) it is Hazard ratio (hazard ratio, HR) less than 1, they are the generations of colorectal cancer
Protective factors in the process；And other 28 marker genes (CDKN2A, NDRG1, FAM3C, CHD2, FZD10, DSG3,
ACSL4,FOXD1,FLT1,KLK5,WSB1,MYOF,KRT6C,GRB10,ANXA2,HOXC6,ITGA3,KRT6A,KRT6B,
MARK3, MSH4, GULP1, KLK7, KLK6, ANXA8, TJP1, PTTG1IP, DLG5) Hazard ratio be greater than 1, they are Colon and rectums
Risk factor in the generating process of cancer.
6) by above-mentioned steps 4) polymolecular marker integrate, being constructed using ssGSEA algorithm can be applied to
The risk scoring model of propertyization prediction Patients with Colorectal Cancer prognosis.The formula of the evaluation model is as follows:
PrognosticScore (S)=ssES (Ggood, S) and-ssES (Gpoor, S)
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor
Molecular marker set, S are any one given single sample, and i is designated position, r (gj) it is that expression value is arranged from high to low
Order obtained after sequence and standardization, w are weight order value, which is set as 3；N is gene detected by single sample
Total number, NGFor the total number of prognosis molecule marker.
7) expression of this 46 polymolecular markers 6) is carried out integration foundation through the above steps can clinical application
Colorectal cancer patients prognosis prediction scoring model, using the median of training set risk score as cut off value, by patient point
For survival result it is good and existence result it is poor, if Prognostic Score < median, disclose the patient prognosis existence result compared with
Difference；If Prognostic Score > median, it is preferable to disclose patient's prognosis existence.
8) by above-mentioned steps 4) polymolecular marker combination and its risk scoring model be respectively applied to three it is independent
In the Patients with Colorectal Cancer data set (TCGA, GSE14333, GSE33113) of different platform, the polymolecular marker combination and its
Risk scoring model can be good at significantly distinguishing the cancer patient progress of high low-risk.
Present invention firstly discovers that a kind of new polymolecular marker combination based on function-driven, the polymolecular marker group
Conjunction can predict the prognosis of colorectal cancer patients.Compared with the existing technology, the superiority of polymolecular marker combination exists
In:
First, the present invention concentrates from the multiple cancer big-sample datas of multicenter while screening prognosis prediction marker, and right
The prediction effect of the polymolecular marker is verified and has been fully assessed in 3 independent data sets, above method and plan
Application slightly ensure that reliability of the present invention in the judgement of colorectal cancer patients prognosis.
Second, polymolecular marker combination not will receive the influence of the batch effect or detection platform difference of experiment,
It ensure that stability of the present invention in the judgement of colorectal cancer patients prognosis.
Third, polymolecular marker combination do not need to carry out the data normalization processing between multisample before use, make
With convenience, clinical operability of the present invention in the judgement of colorectal cancer patients prognosis ensure that.
Every technical staff's notice: of the invention although the present invention is described according to above-mentioned specific embodiment
Invention thought be not limited in the invention, any repacking with inventive concept will all be included in this patent protection of the patent right
In range.
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (3)
1. a kind of polymolecular marker of the individuation prediction colorectal cancer prognosis of function-driven, which is characterized in that described is more
Molecular marker includes that protection factor molecular marker in colorectal cancer generating process of the Hazard ratio less than 1 and Hazard ratio are greater than
Risk factor molecular marker in 1 colorectal cancer generating process, the protection factor molecular marker include 18 marks
Will object gene C EBPA, KLHDC3, FITM2, GALM, CYP1A1, ANKS4B, IL12A, CC2D1A, ZC4H2, PRLR, VANGL2,
NDRG2, CCL22, GORASP1, ST6GAL1, TRAF1, L3MBTL4, ARHGEF11, the risk factor molecular marker packet
28 markers gene C DKN2A, NDRG1, FAM3C, CHD2, FZD10, DSG3, ACSL4, FOXD1, FLT1, KLK5 are included,
WSB1,MYOF,KRT6C,GRB10,ANXA2,HOXC6,ITGA3,KRT6A,KRT6B,MARK3,MSH4,GULP1,KLK7,
KLK6,ANXA8,TJP1,PTTG1IP,DLG5。
2. a kind of using polymolecular marker personalization described in claim 1 prediction Patients with Colorectal Cancer prognostic risk evaluation dress
It sets, which is characterized in that the device includes the risk assessment scoring model for predicting Patients with Colorectal Cancer prognosis, the evaluation
The formula of scoring model is as follows:
Prognostic Score (S)=ssES (Ggood, S) and-ssEE (Gpoor, S)；
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor molecule
Marker set, S are any one given single sample, and i is designated position, r (gj) it is that expression value sorts simultaneously from high to low
Order obtained after standardization, w are weight order value, which is set as 3；N is that gene detected by single sample is always a
Number, NGFor the total number of prognosis molecule marker.
3. it is a kind of using right want 1 described in prediction colorectal cancer prognosis polymolecular marker Patients With Rectal Carcinoma prognosis wind
Dangerous evaluation method, which comprises the following steps:
(1) the colorectal cancer gene expression profile data with clinical information such as life span and survival conditions is obtained, including 9
Patients with Colorectal Cancer microarray data is covered, a set of Patients with Colorectal Cancer RNA-seq expresses data；
(2) using the data set for containing comprehensive life span in the data of acquisition as training set, single Cox and more Cox are utilized respectively
Regression analysis screening has significant associated gene with comprehensive life span；
(3) significant associated gene carries out meta analysis with comprehensive life span for what is recognized in the expression data of acquisition,
Select 69 genes of the p value less than 0.001 as candidate prognosis related molecule marker；
(4) 69 colorectal cancer candidate's prognosis molecule markers of acquisition are subjected to function enrichment analysis, filter out significant enrichment
Candidate molecules marker in GO functional semantics in the relevant semantic entry of biological process, it is pre- as final colorectal cancer
Molecular marker afterwards, totally 46 genes；
(5) 46 of acquisition final colorectal cancer prognosis molecule markers are divided into 18 colorectal cancers of the Hazard ratio less than 1
Protection factor molecular marker gene C EBPA, KLHDC3, FITM2, GALM, CYP1A1, ANKS4B in generating process,
IL12A,CC2D1A,ZC4H2,PRLR,VANGL2,NDRG2,CCL22,GORASP1,ST6GAL1,TRAF1,L3MBTL4,
Risk factor molecular marker gene C DKN2A in colorectal cancer generating process of ARHGEF11 and 28 Hazard ratio greater than 1,
NDRG1,FAM3C,CHD2,FZD10,DSG3,ACSL4,FOXD1,FLT1,KLK5,WSB1,MYOF,KRT6C,GRB10,
ANXA2,HOXC6,ITGA3,KRT6A,KRT6B,MARK3,MSH4,GULP1,KLK7,KLK6,ANXA8,TJP1,PTTG1IP,
DLG5；
(6) the polymolecular marker of above-mentioned steps (5) is integrated, being constructed using ssGSEA algorithm can be applied to individual character
Change the risk scoring model of prediction Patients with Colorectal Cancer prognosis.The formula of the evaluation model is as follows:
Prognostic Score (S)=ssES (Ggood, S) and-ssES (Gpoor, S)；
Wherein, G is prognosis molecule marker set, GgoodFor protection factor molecular marker set, GpoorFor risk factor molecule
Marker set, S are any one given single sample, and i is designated position, r (gj) it is that expression value sorts simultaneously from high to low
Order obtained after standardization, w are weight order value, which is set as 3；N is that gene detected by single sample is always a
Number, NGFor the total number of prognosis molecule marker；
(7) by the expression of this 46 polymolecular markers carry out integration establish can clinical application colorectal cancer patients prognosis
Prediction scoring model, using the median of training set risk score as cut off value, by patient be divided into existence result it is good and survive
As a result poor, if Prognostic Score < median, the prognosis existence result for disclosing the patient is poor；If Prognostic
It is preferable to disclose patient's prognosis existence for Score > median.
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| CN110187107A (en) * | 2019-04-26 | 2019-08-30 | 温州医科大学 | A kind of prognostic evaluation of colorectal carcinoma device and method established based on tumor tissues infiltration immunocyte feature |
| CN111785327A (en) * | 2019-04-04 | 2020-10-16 | 苏州扇贝生物科技有限公司 | Method and device for screening isomiR molecular markers |
| CN112029860A (en) * | 2020-09-03 | 2020-12-04 | 首都医科大学 | Marker molecule related to colorectal cancer prognosis and detection kit |
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| CN113466458A (en) * | 2021-06-29 | 2021-10-01 | 复旦大学附属中山医院 | Application of GPX4, NOX1 and ACSL4 in colorectal cancer prognosis evaluation |
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